The present application relates generally to the treatment of arterial atherosclerotic disease and relates more particularly to techniques for reducing the occurrence of occlusions following treatment for arterial atherosclerotic disease.
Atherosclerosis, which involves the deposition of a fatty plaque on the luminal surface of an artery, is one of the leading causes of death and disability in the world. This is because the deposition of plaque on the luminal surface of an artery causes a narrowing of the cross-sectional area of the artery. Such a narrowing reduces or effectively blocks blood flow distal to the site of the narrowing, causing ischemic damage to those tissues supplied by the artery.
A coronary artery is an artery that supplies the heart with blood. Consequently, a narrowing of the coronary artery lumen comprises the perfusion of heart muscle. This results in angina with exertion or even at rest. A complete occlusion of a vessel results in myocardial infarction, often causing death or subsequent heart failure. Unfortunately, the problem of coronary artherosclerosis is pervasive. There are well over 1.5 million myocardial infarctions in the United States each year. Acute myocardial infarctions result each year in the deaths of hundreds of thousands.
The preferred treatment for coronary atherosclerosis is percutaneous transluminal coronary balloon angioplasty (“PTCA”), with approximately one million such procedures performed each year in the United States alone. In PTCA, a balloon catheter is percutaneously inserted into a peripheral artery and is then threaded through the arterial system into the narrowed coronary artery. The balloon is then inflated so as to expand radially outwardly, thereby flattening the fatty plaque within the narrowed artery against the arterial wall and increasing the cross-sectional flow of blood through the treated coronary artery. Unfortunately, approximately 30–40% of those patients who undergo PTCA suffer from restenosis or a re-narrowing of the treated artery within six months of the procedure.
This restenosis is a response to local injury of the vessel wall by the balloon. Mechanisms of restenosis include (i) constrictive remodeling, likely due to retractile scar formation within the arterial wall, and (ii) the proliferation of smooth muscle cells with accompanying synthesis of extra-cellular matrix. This proliferation occurs in the intima, the layer beneath the inner lining of endothelial cells. (This endothelium is stripped by the angioplasty.) The resulting thickening of the intimal layer (neointima) re-narrows the artery. See e.g., Van Belle et al., “Endothelial regrowth after arterial injury: from vascular repair to therapeutics,” Cardiovascular Research, 38(1): 54–68 (April 1998), which is incorporated herein by reference.
A number of different approaches have been devised to deal with the problem of post-angioplasty restenosis, including treating the patient with various drugs (see e.g., Lefkovits et al., Progress in Cardiovascular Diseases, 40(2):141–58 (September/October 1997), which is incorporated herein by reference), administering radiation to the angioplasty site to inhibit neointimal thickening (see e., Coussement et al., Circulation, 104:2459–64 (2001), which is incorporated herein by reference) or, more successfully, implanting a stent in the artery at the affected site. A stent is a scaffold typically in the form of a tubular metal mesh that is used to mechanically keep an artery open. Although the use of stents has reduced the rate of restenosis to about 20–30%, there is obviously much room for improvement. Moreover, it appears that while stents reduce the risk of restenosis by eliminating constrictive remodeling, stents do not inhibit neointimal proliferation. See e.g., Leon et al., “Localized Intracoronary Gamma-Radiation Therapy to Inhibit the Recurrence of Restenosis After Stenting,” N. Eng. J. Med., 344(4): 250–6 (Jan. 25, 2001); and Farb et al., “Pathology of Acute and Chronic Coronary Stenting in Humans,” Circulation, 99:44–52 (1999); both of which are incorporated herein by reference. In fact, a repeat angioplasty performed on a re-narrowed lesion within a stent has an even higher rate of restenosis—approaching 50%.
Drug-coated stents releasing cytotoxic agents, such as paclitaxel and sirolimus, have shown promising results in relatively short periods of follow-up. However, the long-term outlook for this approach remains unknown at present. In animal models, benefits are shown to be short-lived. See Virmani et al., Herz, 27:1–6 (2002), which is incorporated herein by reference.
In view of the above, it can be readily appreciated that there is a definite need for a technique for minimizing, over the long-term, the occurrence of restenosis in coronary arteries following balloon angioplasty. To accomplish this, it is necessary to prevent or to reduce the proliferation of smooth muscle cells in the neointima, as described above. There is evidence from various animal models that an intact endothelial lining does suppress cell proliferation in the intimal layer beneath. (Van Belle et al., cited above). Furthermore, in experimental models of angioplasty, the local delivery by catheter of endothelial growth factors accelerates endothelial resurfacing and concurrently inhibits intimal hyperplasia. (See Asahara et al., Circulation, 91:2793–801 (1995) and Yasuda et al., Circulation, 101:2546–9 (2000), both of which are incorporated herein by reference.) Therefore, rapid re-endothelialization is widely regarded as an important objective in reducing restenosis. Nevertheless, despite evidence suggesting the desirability of rapid re-endothelialization following angioplasty, an effective means for achieving this objective has not heretofore been provided. By contrast, the natural re-endothelialization of an area of angioplasty takes many weeks, which is far too long to effectively inhibit restenosis. Such natural re-endothelialization is thought to occur principally through the ingrowth of endothelial cells from the edges of the treated area and from the orifices of any small branch arteries within the area of angioplasty.
It should be noted that the narrowing of an artery due to atherosclerosis is not limited to the coronary arteries, but can occur in all other arteries as well. Clinically important sites of disease include the carotid, aortoiliac, superficial femoral, profunda femoris, popliteal, tibial, subclavian and mesenteric arteries. Peripheral vascular disease, i.e., atherosclerotic disease in an artery of the lower limbs, can be treated with a modicum of success using percutaneous transluminal balloon angioplasty (preferably followed by the implantation into the treated artery of a stent). However, the preferred and more successful treatment involves bypassing the narrowed section of the artery using a tubular graft. Such a graft is typically either an autologous venous segment or a synthetic graft. In the case of a synthetic graft, the graft is typically made of polyethylene terephthalate (PET, Dacron) or polytetrafluoroethylene (PTFE) and is additionally often impregnated with a biomolecule, such as collagen, to reduce the microporosity of the graft.
As can be readily appreciated, an autologous venous segment suitable for use as a graft is often unavailable in patients suffering from atherosclerosis. This may be due to venous disease or to prior use in other vascular surgery. Accordingly, the use of a synthetic graft is necessary in many cases. Unfortunately, however, thrombosis or clotting is a very significant problem for synthetic grafts, resulting in low long-term patency rates for synthetic bypass grafts—especially when such grafts are placed below the groin. For example, the five-year patency rate for synthetic grafts placed below the groin and above the knee is approximately 50% (open) and for grafts placed below the knee is approximately 15% (open).
Endothelial cells are the natural lining of blood vessels. These cells produce TPA and other molecules that inhibit thrombosis. It is widely accepted that the development of an endothelial cell lining on the surface of a synthetic graft may prevent thrombosis therewithin. Unfortunately, however, no practical method has yet been devised for forming such a layer of endothelial cells on a synthetic graft. Clinical studies of the effects of endothelialization on graft patency have depended on harvesting endothelial cells from the patient (e.g., from an excised vein), growing them in tissue culture, and then seeding them onto the graft before surgery. See e.g., Laube et al., The Journal of Thoracic and Cardiovascular Surgery, 120(1):134–41 (July 2000); Deutsch et al., Surgery, 126(5):847–55 (November 1999); Fujita et al., Ann. Vasc. Surg., 13(4):402–12 (1999); Salacinski et al., Med. Biol. Eng. Comput., 39:609–18 (2001); Ozaki et al., J. Vasc. Surg., 18:486–94 (1993); Carr et al., Ann. Vasc. Surg., 10:469–75 (1996); Vinard et al., Ann. Vasc. Surg., 13:141–50 (1999); and Bhattacharya et al., Blood, 95(2):581–5 (Jan. 15, 2000), all of which are incorporated herein by reference. The seeded graft is then implanted into the patient.
As can readily be appreciated, the approach described above is most demanding, laborious, and time-consuming and is not at all suitable for general use. Nevertheless, the benefits of graft endothelialization have been demonstrated. For instance, in the study by Deutsch et al. cited above, the 9-year patency rate was 65% for endothelialized infrainguinal (below groin) grafts compared with 16% patency in the control group.
In U.S. Patent Application Publication No. US 2002/0049495, which was published Apr. 25, 2002, and which is incorporated herein by reference, there is disclosed a coating composition that is applied in the production of a medical device, such as a stent or a synthetic graft, to promote the adherence of endothelial cells to the medical device. According to said published patent application, the coating composition comprises a matrix incorporating monospecific antibodies reactive with endothelial cells. The matrix may be composed of a synthetic material, such as fullerenes, polyurethane, poly-L-lactic acid, cellulose ester or polyethylene glycol, or may be composed of a naturally occurring material, such as collagen, fibrin, elastin or amorphous carbon. The matrix may comprise several layers, with a first layer being composed of synthetic or naturally occurring materials and a second layer composed of antibodies. The matrix may be covalently or non-covalently attached to the medical device, with the antibodies being covalently attached to the matrix using hetero- or homobifunctional cross-linking reagents. To bind endothelial cells to the thus-coated medical device, the coated medical device is incubated in the presence of endothelial cells.
The present inventors have noted certain significant shortcomings with the technique of the aforementioned published patent application. First, to the extent that the subject published patent application teaches using a coated stent, by itself, to seed endothelialization, such an approach will likely be insufficient because a stent, which is a wire mesh, covers only a very small percentage of a denuded arterial surface and, therefore, provides only a minimal surface area for the attachment of cells.
In addition, because a deployed stent recoils outwardly, pressing against its surrounding arterial wall, the struts of the stent are effectively buried in furrows of the luminal surface, even breaking through that surface in many cases. As a result, the stent struts are not well enough exposed to blood in the lumen for efficient capture of endothelial cells from the blood.
Insofar as the above-mentioned published patent application relates to synthetic grafts, the technique specified therein also suffers from the shortcoming that it requires that currently commercially available graft materials first be modified by the application thereto of an antibody-containing coating matrix in order to be made ready for endothelialization. In other words, such a technique does not permit the endothelialization of off-the-shelf graft materials as they are.
An additional concern of the technique described in the subject published patent application relates to the efficacy of the antibody incorporated into the coating matrix applied to the medical device. These antibody molecules may be sterically constrained by noncovalent interactions with other matrix components so that their antigen binding sites are not freely available for binding cells in the blood.